EP3903809A1 - Botulinum toxin pharmaceutical composition comprising tannic acid - Google Patents
Botulinum toxin pharmaceutical composition comprising tannic acid Download PDFInfo
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- EP3903809A1 EP3903809A1 EP20202355.2A EP20202355A EP3903809A1 EP 3903809 A1 EP3903809 A1 EP 3903809A1 EP 20202355 A EP20202355 A EP 20202355A EP 3903809 A1 EP3903809 A1 EP 3903809A1
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- Prior art keywords
- botulinum toxin
- tannic acid
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- botox
- tannylated
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Definitions
- the present invention relates to a botulinum toxin pharmaceutical composition
- a botulinum toxin pharmaceutical composition comprising tannic acid as an active ingredient.
- Botulinum toxin a potent polypeptide neurotoxin. Neuroparalysis in humans and animals occurs 18 to 36 hours after eating food infected with botulinum toxin or spores.
- Botulinum toxin structure consists of a heavy chain and a light chain. This toxin passes through the intestinal lining without reducing toxicity, binds to the synaptic vesicle protein exposed during exocytosis of the presynaptic terminal of peripheral motor neurons, and enters the peripheral motor neurons through endocytotic vesicles by clathrin. Due to the high internal acidity of the endocytotic vesicles, the light chain of the botulinum toxin is released into the cytoplasm.
- the light chain in the cytoplasm has a zinc endopeptidase function, so it attacks vesicle proteins.
- acetylcholine a neurotransmitter
- the release of acetylcholine, a neurotransmitter is suppressed, leading to symptoms of botulinum toxin poisoning, such as gait disturbance, dysphagia, speech disorder, respiration muscle paralysis, etc., and may lead to death.
- the molecular weight of the botulinum toxin protein is about 150 kDa, and there are seven botulinum toxins known to date (A, B, C, D, E, F and G).
- the botulinum toxin is released by Clostridium bacteria as a complex containing a 150 kDa botulinum toxin protein molecule along with a non-toxic protein. Therefore, the botulinum toxin type A complex can be produced by Clostridium bacteria as the forms of 900, 500 and 300 kDa.
- the botulinum toxin types B and C are produced as a 500 kDa complex, and the botulinum toxin type D is produced as 300 kD and 500 kDa complexes.
- the botulinum toxin types E and F are produced only as a 300 kD complex.
- the composition of the complexes is believed to include a non-toxic and non-hemagglutinin protein structure and a hemagglutinin protein.
- the complex composition includes a non-toxic non-hemagglutinin protein structure and an erythrocyte agglutinin protein. These two non-toxic proteins act to provide stability against botulinum toxin molecule denaturation and protection against digestive acids when the toxin is ingested. It is known that the larger the botulinum toxin complex, the more slowly the botulinum toxin spreads from the intramuscular injection site.
- the complex When the toxin complex is treated with erythrocytes at pH 7.3, the complex can be separated into a toxin protein and a hemagglutinin protein. When the hemagglutinin protein is separated, the toxin protein becomes significantly unstable.
- BOTOX® Allergan, Inc., 900 kDa full accessory protein complex
- Jeuveau 900 kDa full accessory protein complex
- Dysport Undisclosed complex
- Xeomin 150 kDa no accessory proteins
- Medytox Medytox
- Botulax Hugel
- the composition of most BOTOX®, Jeuveau, Dysport, Medytox and Botulax consists of the purified botulinum toxin type A complex, albumin and sodium chloride, which packaged in sterile, vacuum-dried form.
- the botulinum toxin type A is prepared from a culture of the Clostridium botulinum Hall strain cultured in a medium containing N-Z amine and yeast extract.
- the botulinum toxin type A complex is purified from a culture solution through a series of acid precipitation into a crystalline complex consisting of an active high molecular weight toxin protein and a related hemagglutinin protein.
- the crystalline complex is re-dissolved in brine and albumin, filter sterilized (0.2 micron), and vacuum dried.
- Botulinum toxin is used in clinical settings for the treatment of neuromuscular disorders characterized by spasticity (hyperactive skeletal muscle) caused by cerebral palsy and stroke.
- the botulinum toxin type A was approved by the US Food and Drug Administration in 1989 for the treatment of essential blepharospasm, strabismus and hemifacial spasm in patients 12 years of age or older.
- the clinical effect of the botulinum toxin type A injected into the peripheral muscle usually occurs within 1 week after the injection.
- the typical duration of symptom relief (ie, relaxed muscle paralysis) by a single intramuscular injection of botulinum toxin type A is about 3 months. Recently, it has been widely used as a wrinkle improvement treatment to improve women's wrinkles.
- Patent reference 1 (Korean Patent No. 10-2088104 ) is an example of using Erigeron annuus flower essential oil as a Botox adjuvant for the purpose of increasing the medicinal effect of Botox. More specifically, the patent reference 1 aims to extend the duration of maintenance of the botulinum neurotoxin effect by further including Erigeron annuus flower essential oil in the botulinum neurotoxin composition, and this was confirmed through the maintenance period of muscle paralysis. However, the patent reference 1 does not disclose the necessity of reducing side effects caused by diffusion in vivo without staying at the injection site of Botox mentioned above and solutions for minimizing the side effects at all.
- the present inventors have conducted studies to derive an adjuvant that can not only improve the activity of Botox itself, but also minimize the side effects that occur when Botox is diffused from the injection site, and a composition containing the same.
- the botulinum toxin pharmaceutical composition comprising tannic acid provided in one aspect of the present invention improves the activity of the botulinum neurotoxin itself, allows the botulinum neurotoxin to stay in the injected place, and prevents the botulinum neurotoxin from spreading to the blood due to the properties of tannic acid.
- the present inventors have completed the present invention by confirming the effect of minimizing the side effects of the conventional Botox caused by the spread of the botulinum neurotoxin.
- It is another object of the present invention to provide a pharmaceutical composition comprising Botulinum toxin (Botox); and tannic acid (TA) as active ingredients.
- Botulinum toxin Botox
- TA tannic acid
- It is another object of the present invention to provide a method for treating neuromuscular related diseases comprising a step of administering a pharmaceutically effective amount of a tannylated botulinum toxin complex containing botulinum toxin (Botox) and tannic acid (TA) to a subject in need.
- a tannylated botulinum toxin complex containing botulinum toxin (Botox) and tannic acid (TA) to a subject in need.
- It is another object of the present invention to provide a pharmaceutical composition comprising botulinum toxin (Botox); and tannic acid (TA) as active ingredients, for use in preventing or treating neuromuscular related diseases.
- Botox botulinum toxin
- TA tannic acid
- Botox botulinum toxin
- TA tannic acid
- It is another object of the present invention to provide a cosmetic composition comprising Botulinum toxin (Botox); and tannic acid (TA) as active ingredients.
- Botulinum toxin Botox
- TA tannic acid
- It is another object of the present invention to provide a method for treating cosmetic defect comprising a step of administering a (cosmetically) effective amount of a tannylated botulinum toxin complex containing botulinum toxin (Botox) and tannic acid (TA) to a subject in need.
- Botox botulinum toxin
- TA tannic acid
- TA tannic acid
- Botulinum toxin (Botox) adjuvant comprising tannic acid (TA) as an active ingredient.
- the present invention provides a tannylated botulinum toxin complex comprising botulinum toxin (Botox) and tannic acid (TA).
- Botox botulinum toxin
- TA tannic acid
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising botulinum toxin (Botox); and tannic acid (TA) as active ingredients.
- Botox botulinum toxin
- TA tannic acid
- the present invention provides a method for treating neuromuscular related diseases comprising a step of administering a pharmaceutically effective amount of a tannylated botulinum toxin complex containing botulinum toxin (Botox) and tannic acid (TA) to a subject in need.
- a tannylated botulinum toxin complex containing botulinum toxin (Botox) and tannic acid (TA) to a subject in need.
- the present invention provides a use of the tannylated botulinum toxin complex containing botulinum toxin (Botox) and tannic acid (TA) to prepare a medicament for the treatment of neuromuscular related diseases.
- Botox botulinum toxin
- TA tannic acid
- the present invention provides a cosmetic composition
- a cosmetic composition comprising botulinum toxin (Botox); and tannic acid (TA) as active ingredients.
- Botox botulinum toxin
- TA tannic acid
- the present invention provides a method for treating cosmetic defect comprising a step of administering a pharmaceutically effective amount of a tannylated botulinum toxin complex containing botulinum toxin (Botox) and tannic acid (TA) to a subject in need.
- a pharmaceutically effective amount of a tannylated botulinum toxin complex containing botulinum toxin (Botox) and tannic acid (TA) to a subject in need.
- the present invention provides a use of the tannylated botulinum toxin complex containing botulinum toxin (Botox) and tannic acid (TA) to prepare a medicament for the treatment of cosmetic defect.
- Botox botulinum toxin
- TA tannic acid
- the present invention provides a botulinum toxin (Botox) adjuvant comprising tannic acid (TA) as an active ingredient.
- Botox botulinum toxin
- TA tannic acid
- the botulinum toxin pharmaceutical composition comprising tannic acid provided in one aspect of the present invention improves the activity of the botulinum neurotoxin itself, allows the botulinum neurotoxin to stay in the injected place, and prevents the botulinum neurotoxin from spreading to the blood due to the properties of tannic acid. Therefore, the composition of the present invention has an effect of minimizing the side effects of the conventional Botox caused by the spread of the botulinum neurotoxin.
- the present invention provides a tannylated botulinum toxin complex comprising botulinum toxin (Botox) and tannic acid (TA).
- Botox botulinum toxin
- TA tannic acid
- the tannic acid is characterized by being tannylated by binding to the botulinum toxin.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising botulinum toxin (Botox); and tannic acid (TA) as active ingredients.
- Botox botulinum toxin
- TA tannic acid
- the tannic acid is characterized by being tannylated by binding to the botulinum toxin.
- the pharmaceutical composition can be used for preventing or treating neuromuscular related diseases.
- the molecular weight of the botulinum toxin protein is about 150 kDa, and there are seven botulinum toxins known to date (A, B, C, D, E, F and G).
- the botulinum toxin is released by Clostridium bacteria as a complex containing a 150 kDa botulinum toxin protein molecule along with a non-toxic protein. Therefore, the botulinum toxin type A complex can be produced by Clostridium bacteria as the forms of 900, 500 and 300 kDa.
- the botulinum toxin types B and C are produced as a 500 kDa complex, and the botulinum toxin type D is produced as 300 kD and 500 kDa complexes.
- the botulinum toxin types E and F are produced only as a 300 kD complex.
- the composition of the complexes includes a non-toxic and non-hemagglutinin protein structure and a hemagglutinin protein.
- the botulinum toxin can be a botulinum neurotoxin type A (BoNT/A).
- the botulinum toxin can be included in the composition in a concentration range of 5 to 10,000 U/ml, but is not particularly limited to the concentration range, and the concentration range can be appropriately adjusted according to the purpose of use of the composition.
- concentration ranges may be, for example, a concentration range of 5 to 8,000 U/ml, a concentration range of 5 to 6,000 U/ml, a concentration range of 5 to 4,000 U/ml, a concentration range of 5 to 2,000 U/ml, a concentration range of 5 to 1,000 U/ml, a concentration range of 5 to 900 U/ml, a concentration range of 5 to 800 U/ml, a concentration range of 5 to 700 U/ml, a concentration range of 5 to 600 U/ml, a concentration range of 5 to 500 U/ml, a concentration range of 5 to 400 U/ml, a concentration range of 5 to 300 U/ml, a concentration range of 5 to 200 U/ml, a concentration range of 5 to 100 U/ml, a concentration range of 5 to 90 U/ml, a concentration range of 5 to 80 U/ml, a concentration range of 5 to 70 U/ml, a concentration range of 5 to 60 U/ml, and
- Tannic acid is one of the most abundant polyphenols found in plants such as fruits, vegetables, olives, and cacao. Recently, tannic acid is used as a multifunctional coating molecule.
- TA is known as a molecule having excellent affinity with biomacromolecules including DNA and proline-rich proteins such as thrombin, gelatin, collagen and mucin. Tannic acid can bind to proteins through multiple hydrogen bonds and hydrophobic interactions between the phenolic hydroxyl group rich moiety (5 gallol groups (3 -OH groups linked to an aromatic ring) and 5 catechol groups (2 -OH groups covalently linked to an aromatic ring)) and the target protein.
- the tannic acid (TA) can be used in an appropriate amount depending on the amount of botulinum toxin in the composition and/or maximizing the activity of the botulinum toxin itself or minimizing side effects.
- the tannic acid can be included in the composition at a concentration range of 10 nM to 500 ⁇ M.
- the tannic acid can be included in the composition at a concentration range of 10 nM to 480 ⁇ M, at a concentration range of 10 nM to 460 ⁇ M, at a concentration range of 10 nM to 440 ⁇ M, at a concentration range of 10 nM to 420 ⁇ M, at a concentration range of 10 nM to 400 ⁇ M, at a concentration range of 10 nM to 380 ⁇ M, at a concentration range of 10 nM to 360 ⁇ M, at a concentration range of 10 nM to 340 ⁇ M, at a concentration range of 10 nM to 320 ⁇ M, at a concentration range of 10 nM to 460 ⁇ M, at a concentration range of 10 nM to 300 ⁇ M, at a concentration range of 10 nM to 280 ⁇ M, at a concentration range of 10 nM to 260 ⁇ M, at a concentration range of 10 nM to 240 ⁇ M, at a concentration range of 10
- the neuromuscular related disease can be selected from the group consisting of myoclonus, hemifacial spasm, spasmodic torticollis, anal fissure, blepharospasm, facial spasm, cerebral palsy, medication overuse headache, chronic migraine, myalgia, strabismus, temporomandibular disorder, neuralgia, overactive bladder, urge urinary incontinence, rhinitis, acne, dystonia, hyperhidrosis and vocal fold granuloma.
- TA tannic acid
- the present invention provides a pharmaceutical kit for preventing or treating neuromuscular related diseases comprising a first component containing botulinum toxin (Botox); and a second component containing tannic acid (TA).
- Botox botulinum toxin
- TA tannic acid
- the botulinum toxin can be included in the first component in a concentration range of 5 to 10,000 U/ml, but is not particularly limited to the concentration range, and the concentration range can be appropriately adjusted according to the purpose of use of the kit.
- several concentration ranges may be, for example, a concentration range of 5 to 8,000 U/ml, a concentration range of 5 to 6,000 U/ml, a concentration range of 5 to 4,000 U/ml, a concentration range of 5 to 2,000 U/ml, a concentration range of 5 to 1,000 U/ml, a concentration range of 5 to 900 U/ml, a concentration range of 5 to 800 U/ml, a concentration range of 5 to 700 U/ml, a concentration range of 5 to 600 U/ml, a concentration range of 5 to 500 U/ml, a concentration range of 5 to 400 U/ml, a concentration range of 5 to 300 U/ml, a concentration range of 5 to 200 U/ml, a concentration range of 5 to 100 U/
- the tannic acid in the second component, can be used in an appropriate amount depending on the amount of botulinum toxin in the kit and/or maximizing the activity of the botulinum toxin itself or minimizing side effects.
- the tannic acid can be included in the second component at a concentration range of 10 nM to 500 ⁇ M.
- the tannic acid can be included in the component at a concentration range of 10 nM to 480 ⁇ M, at a concentration range of 10 nM to 460 ⁇ M, at a concentration range of 10 nM to 440 ⁇ M, at a concentration range of 10 nM to 420 ⁇ M, at a concentration range of 10 nM to 400 ⁇ M, at a concentration range of 10 nM to 380 ⁇ M, at a concentration range of 10 nM to 360 ⁇ M, at a concentration range of 10 nM to 340 ⁇ M, at a concentration range of 10 nM to 320 ⁇ M, at a concentration range of 10 nM to 460 ⁇ M, at a concentration range of 10 nM to 300 ⁇ M, at a concentration range of 10 nM to 280 ⁇ M, at a concentration range of 10 nM to 260 ⁇ M, at a concentration range of 10 nM to 240 ⁇ M, at a concentration range of 10
- the present invention provides a method for improving the activity of botulinum toxin, comprising a step of tannylating the botulinum toxin by treating the botulinum toxin (Botox) with tannic acid (TA).
- Botox botulinum toxin
- TA tannic acid
- the present invention provides a method for reducing the side effects caused by in vivo diffusion of botulinum toxin, comprising a step of tannylating the botulinum toxin by treating the botulinum toxin (Botox) with tannic acid (TA).
- Botox botulinum toxin
- TA tannic acid
- the present invention provides a method for treating neuromuscular related diseases comprising a step of administering a pharmaceutically effective amount of a tannylated botulinum toxin complex containing botulinum toxin (Botox) and tannic acid (TA) to a subject in need.
- the administration is not particularly limited to oral/parenteral administration, but administration by injection is preferred.
- the present invention provides a use of the tannylated botulinum toxin complex containing botulinum toxin (Botox) and tannic acid (TA) to prepare a medicament for the treatment of neuromuscular related diseases.
- Botox botulinum toxin
- TA tannic acid
- the present invention provides a cosmetic composition comprising botulinum toxin (Botox); and tannic acid (TA) .
- Botox botulinum toxin
- TA tannic acid
- the cosmetic effect of the cosmetic composition may be one or more selected from the group consisting of reduced appearance of fine lines, reduced appearance of wrinkles, widening of the eyes, lifting the corner of the mouth, decrease in muscle mass and flattening of the lines extending from the upper lip.
- the botulinum toxin can be included in the composition in a concentration range of 5 to 10,000 U/ml, but is not particularly limited to the concentration range, and the concentration range can be appropriately adjusted according to the purpose of use of the cosmetic composition.
- several concentration ranges may be, for example, a concentration range of 5 to 8,000 U/ml, a concentration range of 5 to 6,000 U/ml, a concentration range of 5 to 4,000 U/ml, a concentration range of 5 to 2,000 U/ml, a concentration range of 5 to 1,000 U/ml, a concentration range of 5 to 900 U/ml, a concentration range of 5 to 800 U/ml, a concentration range of 5 to 700 U/ml, a concentration range of 5 to 600 U/ml, a concentration range of 5 to 500 U/ml, a concentration range of 5 to 400 U/ml, a concentration range of 5 to 300 U/ml, a concentration range of 5 to 200 U/ml, a concentration range of 5 to 100 U/
- the tannic acid (TA) can be used in an appropriate amount depending on the amount of botulinum toxin in the composition and/or maximizing the activity of the botulinum toxin itself or minimizing side effects.
- the tannic acid can be included in the composition at a concentration range of 10 nM to 500 ⁇ M.
- the tannic acid can be included in the composition at a concentration range of 10 nM to 480 ⁇ M, at a concentration range of 10 nM to 460 ⁇ M, at a concentration range of 10 nM to 440 ⁇ M, at a concentration range of 10 nM to 420 ⁇ M, at a concentration range of 10 nM to 400 ⁇ M, at a concentration range of 10 nM to 380 ⁇ M, at a concentration range of 10 nM to 360 ⁇ M, at a concentration range of 10 nM to 340 ⁇ M, at a concentration range of 10 nM to 320 ⁇ M, at a concentration range of 10 nM to 460 ⁇ M, at a concentration range of 10 nM to 300 ⁇ M, at a concentration range of 10 nM to 280 ⁇ M, at a concentration range of 10 nM to 260 ⁇ M, at a concentration range of 10 nM to 240 ⁇ M, at a concentration range of 10
- the present invention provides a method for treating cosmetic defect comprising a step of administering a pharmaceutically effective amount of a tannylated botulinum toxin complex containing botulinum toxin (Botox) and tannic acid (TA) to a subject in need.
- the administration is not particularly limited to oral/parenteral administration, but administration by injection is preferred.
- the cosmetic defect can be wrinkle.
- the present invention provides a use of the tannylated botulinum toxin complex containing botulinum toxin (Botox) and tannic acid (TA) to prepare a medicament for the treatment of cosmetic defect.
- Botox botulinum toxin
- TA tannic acid
- the present invention provides a botulinum toxin (Botox) adjuvant comprising tannic acid (TA) as an active ingredient.
- Botox botulinum toxin
- TA tannic acid
- the botulinum toxin (Botox) adjuvant can be used for the prevention or treatment of neuromuscular related diseases selected from the group consisting of myoclonus, hemifacial spasm, spasmodic torticollis, anal fissure, blepharospasm, facial spasm, cerebral palsy, medication overuse headache, chronic migraine, myalgia, strabismus, temporomandibular disorder, neuralgia, overactive bladder, urge urinary incontinence, rhinitis, acne, dystonia, hyperhidrosis and vocal fold granuloma.
- neuromuscular related diseases selected from the group consisting of myoclonus, hemifacial spasm, spasmodic torticollis, anal fissure, blepharospasm, facial spasm, cerebral palsy, medication overuse headache, chronic migraine, myalgia, strabismus, temporomandibular disorder, neuralgia, overactive bladder
- botulinum toxin (Botox) adjuvant can be used for cosmetic purposes.
- the botulinum toxin (Botox) adjuvant can be administered simultaneously with botulinum toxin.
- the botulinum toxin pharmaceutical composition comprising tannic acid provided in one aspect of the present invention improves the activity of the botulinum neurotoxin itself, allows the botulinum neurotoxin to stay in the injected place, and prevents the botulinum neurotoxin from spreading to the blood due to the properties of tannic acid. Therefore, the composition of the present invention has an effect of minimizing the side effects of the conventional Botox caused by the spread of the botulinum neurotoxin.
- the pharmaceutical composition according to the present invention comprising botulinum toxin as an active ingredient can minimize side effects by reducing the spread of the botulinum toxin from the sites of high efficiency targeted treatment and intramuscular injection. This is directly supported by the experimental examples described below.
- tannic acid could deliver proteins into cells by taking advantage of its high binding power to proteins. Because proteins are hydrophilic, they must have receptors or channels for the protein to be delivered into cells. Since tannic acid can bind to all proteins, free OH groups remaining after the binding of tannic acid to proteins can also bind to various proteins in the cell membrane. Cells continue to undergo repetitive endocytosis and exocytosis. If a protein bound to tannic acid binds to the cell membrane, it can be introduced into the cell through endocytosis. The present inventors confirmed whether a mixture of tannic acid and protein was introduced into cells.
- Figure 1 is a set of photographs showing the results of comparing and evaluating the degree of endocytosis of a green fluorescent protein into cells when CHO (Chinese Hamster Ovary) cells were treated with a green fluorescent protein (GFP) alone or a tannylated fluorescent protein prepared by mixing GFP and tannic acid.
- GFP green fluorescent protein
- the electrophysiological measurement was performed as follows to evaluate whether the activity of the botulinum toxin itself was increased when botulinum toxin was tannylated by mixing botulinum toxin (BTX) and tannic acid.
- the electrophysiological measurement method and results are as follows.
- Axion MEA measurement was performed as follows. Before the neuron culture solution was treated with botulinum toxin (BTX), burst frequency and network burst frequency were recorded. 24 hours after the treatment with the botulinum toxin, burst frequency and network burst frequency were recorded again. The results before and after the treatment were compared.
- BTX botulinum toxin
- Figure 2 is a diagram showing the results of patch-clamp of the group treated with botulinum toxin (BTX) alone (corresponding to BoNT 50U in the diagram) and the group treated with botulinum toxin (BTX) tannylated by treating tannic acid (TA) (corresponding to BoNT 50U / TA 250 nM in the diagram).
- BTX botulinum toxin
- TA tannic acid
- Figure 3 is a set of graphs showing the results of deriving LogIC 50 values for each treatment concentration of botulinum toxin from the results of patch-clamp of the group treated with botulinum toxin (BTX) alone (corresponding to BoNT Treatment in the diagram) and the group treated with botulinum toxin (BTX) tannylated by treating tannic acid (TA) (corresponding to BoNT/TA Treatment in the diagram).
- BTX botulinum toxin
- TA tannic acid
- Figure 4 is a set of graphs showing the results of recording burst frequencies and network burst frequencies of the group treated with tannic acid (TA) alone (corresponding to TA[250] in the diagram), the group treated with botulinum toxin (BTX) alone (corresponding to B[5], B[10] and B[25] in the diagram) and the group treated with botulinum toxin (BTX) tannylated by treating tannic acid (TA) (corresponding to B-T[5], B-T[10] and B-T[25] in the diagram) from Axion MEA data.
- the concentration unit is nM
- B the concentration unit is U (unit)
- the value in [] of B-T is the concentration of B
- the TA concentration was fixed at 250 nM.
- B[5] means that the concentration of the botulinum toxin was 5 U/ml
- B[10] means that the concentration of the botulinum toxin was 10 U/ml
- B [25] means that the concentration of the botulinum toxin was 25 U/ml.
- botulinum toxin In order to evaluate whether not only the activity of the botulinum toxin itself is increased but also the side effects that occurred when the botulinum toxin was injected intradermally can be reduced when the botulinum toxin is tannylated by mixing botulinum toxin (BTX) and tannic acid, the following experiment was performed.
- BTX botulinum toxin
- FIG. 5 is a diagram showing the experimental process of an in vivo experiment evaluating whether the side effects caused by intradermally injecting botulinum toxin can be reduced when botulinum toxin is tannylated by mixing botulinum toxin (BTX) and tannic acid.
- BTX botulinum toxin
- Figure 6 is a set of graphs showing the results of comparing the possibility of causing side effects by expanding botulinum toxin through blood vessels from the injection site by measuring CMAP electrical waveforms at the injection site and the non-injection site (Vehicle) in the group injected with botulinum toxin (BTX) alone (corresponding to BoNT/A only in the diagram) and the group injected with a mixture of botulinum toxin and tannic acid (corresponding to BoNT/A + TA in the diagram).
- the CMAP electrical waveforms at both the injection site and the non-injection site were decreased in the group injected with the botulinum neurotoxin alone (left graph). From the above results, it was confirmed that the botulinum neurotoxin could spread through blood vessels from the injection site, and the botulinum neurotoxin could cause side effects even in unintended places.
- the CMAP electrical waveforms at the injection site were decreased but the CMAP electrical waveforms at the non-injection site (Vehicle) did not decrease in the group injected with a mixture (composition) containing botulinum neurotoxin and tannic acid (right graph). From the above results, it was confirmed that the tannylated botulinum neurotoxin stayed well in the injected place and it was prevented from spreading to the blood due to the properties of tannic acid, which has high protein-binding ability, so that the side effects of the conventional Botox caused by the spread of the botulinum neurotoxin could be minimized.
- Injectable solutions were prepared by mixing all the above components, putting the mixture into 2 ml ampoules by the conventional method for preparing injectable solutions.
- Tannylated botulinum toxin complex 10 mg Isomerized sugar 10 g Mannitol 5 g Purified water proper amount
- the botulinum toxin pharmaceutical composition comprising tannic acid provided in one aspect of the present invention improves the activity of the botulinum neurotoxin itself, allows the botulinum neurotoxin to stay in the injected place, and prevents the botulinum neurotoxin from spreading to the blood due to the properties of tannic acid. Therefore, the composition of the present invention has an effect of minimizing the side effects of the conventional Botox caused by the spread of the botulinum neurotoxin.
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WO2020010171A1 (en) * | 2018-07-06 | 2020-01-09 | Elastogenesis, Llc | Dermal compositions and methods of use |
KR102088104B1 (ko) | 2018-06-29 | 2020-03-11 | 호서대학교 산학협력단 | 개망초 꽃 에센셜 오일을 포함하는 신경 근육 관련 질환 예방 및 치료용 조성물 |
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AU1648901A (en) * | 1999-11-29 | 2001-06-12 | Japan Science And Technology Corporation | Neutralizing agent for toxin of microorganism belonging to the genus clostridium |
US8119109B2 (en) * | 2002-10-25 | 2012-02-21 | Foamix Ltd. | Foamable compositions, kits and methods for hyperhidrosis |
CA2552442A1 (en) * | 2002-12-31 | 2004-06-30 | Avon Products, Inc. | Compositions and delivery methods for the treatment of wrinkles, fine lines and hyperhidrosis |
BRPI0618753A2 (pt) * | 2005-11-17 | 2011-09-13 | Revance Therapeutics Inc | composição para liberação transdérmica de toxina botulìnica e método de administração |
EP2072039A1 (en) * | 2007-12-21 | 2009-06-24 | Merz Pharma GmbH & Co.KGaA | Use of a neurotoxic component of Clostridium botulinum toxin complex to reduce or prevent side effects |
JP4232850B1 (ja) * | 2008-01-28 | 2009-03-04 | 学校法人北里研究所 | 麻痺性貝毒成分の除去 |
US20140242110A1 (en) * | 2013-02-28 | 2014-08-28 | Dt Scimed, Llc | Dose, localization, and formulation of botulinum toxins in skin and muscle |
JP6955491B2 (ja) * | 2015-10-29 | 2021-10-27 | ルバンス セラピュティックス インク.Revance Therapeutics,Inc. | 治療効果又は美容効果の長い持続時間を有する、注射用ボツリヌス毒素製剤及びこれらの使用方法 |
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